chr6-161386823-C-G

Variant names:

• chr6-161386823-C-G
• rs1801582
• NM_004562.3:c.1138G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004562.3(PRKN):​c.1138G>C​(p.Val380Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,612,592 control chromosomes in the GnomAD database, including 24,035 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V380I) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.17 (2258 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21777 hom.)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.121
• Publications: 86 publications found

Genes affected

PRKN (HGNC:8607): (parkin RBR E3 ubiquitin protein ligase) The precise function of this gene is unknown; however, the encoded protein is a component of a multiprotein E3 ubiquitin ligase complex that mediates the targeting of substrate proteins for proteasomal degradation. Mutations in this gene are known to cause Parkinson disease and autosomal recessive juvenile Parkinson disease. Alternative splicing of this gene produces multiple transcript variants encoding distinct isoforms. Additional splice variants of this gene have been described but currently lack transcript support. [provided by RefSeq, Jul 2008]

PRKN Gene-Disease associations (from GenCC):

• autosomal recessive juvenile Parkinson disease 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
• Parkinson disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• young-onset Parkinson disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005556226).
• BP6: Variant 6-161386823-C-G is Benign according to our data. Variant chr6-161386823-C-G is described in ClinVar as Benign. ClinVar VariationId is 41221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004562.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKN	NM_004562.3	MANE Select	c.1138G>C	p.Val380Leu	missense	Exon 10 of 12	NP_004553.2
	PRKN	NM_013987.3		c.1054G>C	p.Val352Leu	missense	Exon 9 of 11	NP_054642.2
	PRKN	NM_013988.3		c.691G>C	p.Val231Leu	missense	Exon 7 of 9	NP_054643.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKN	ENST00000366898.6	TSL:1 MANE Select	c.1138G>C	p.Val380Leu	missense	Exon 10 of 12	ENSP00000355865.1
	PRKN	ENST00000366897.5	TSL:1	c.1054G>C	p.Val352Leu	missense	Exon 9 of 11	ENSP00000355863.1
	PRKN	ENST00000366896.5	TSL:1	c.691G>C	p.Val231Leu	missense	Exon 7 of 9	ENSP00000355862.1

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25661 AN: 151948 Hom.: 2245 Cov.: 32

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.0848

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.187

GnomAD2 exomes AF: 0.164 AC: 41277 AN: 251460 AF XY: 0.170

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.224

Gnomad EAS exome AF: 0.0786

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.168 AC: 245829 AN: 1460526 Hom.: 21777 Cov.: 32 AF XY: 0.171 AC XY: 124202 AN XY: 726674

African (AFR) AF: 0.170 AC: 5703 AN: 33450

American (AMR) AF: 0.122 AC: 5440 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 5780 AN: 26130

East Asian (EAS) AF: 0.0744 AC: 2952 AN: 39690

South Asian (SAS) AF: 0.262 AC: 22630 AN: 86222

European-Finnish (FIN) AF: 0.151 AC: 8054 AN: 53416

Middle Eastern (MID) AF: 0.155 AC: 891 AN: 5762

European-Non Finnish (NFE) AF: 0.166 AC: 184217 AN: 1110790

Other (OTH) AF: 0.168 AC: 10162 AN: 60342

GnomAD4 genome AF: 0.169 AC: 25718 AN: 152066 Hom.: 2258 Cov.: 32 AF XY: 0.169 AC XY: 12564 AN XY: 74296

African (AFR) AF: 0.177 AC: 7355 AN: 41468

American (AMR) AF: 0.159 AC: 2424 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 770 AN: 3470

East Asian (EAS) AF: 0.0846 AC: 437 AN: 5164

South Asian (SAS) AF: 0.269 AC: 1293 AN: 4814

European-Finnish (FIN) AF: 0.151 AC: 1598 AN: 10574

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.164 AC: 11180 AN: 67984

Other (OTH) AF: 0.194 AC: 409 AN: 2112

Alfa AF: 0.155 Hom.: 1469

Bravo AF: 0.166

TwinsUK AF: 0.166 AC: 616

ALSPAC AF: 0.169 AC: 653

ESP6500AA AF: 0.185 AC: 816

ESP6500EA AF: 0.171 AC: 1470

ExAC AF: 0.165 AC: 19982

Asia WGS AF: 0.201 AC: 703 AN: 3478

EpiCase AF: 0.166

EpiControl AF: 0.177

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	Autosomal recessive juvenile Parkinson disease 2 (2)
-	-	1	Lung cancer;C0919267:Ovarian neoplasm;C1868675:Autosomal recessive juvenile Parkinson disease 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.69
DANN	Benign	0.26
DEOGEN2	Benign	0.068	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00032	N
LIST_S2	Benign	0.059	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.12
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.28
Sift	Benign	0.38	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.030
MutPred		0.099		Gain of helix (P = 0.0199)
MPC		0.055
ClinPred		0.010	T
GERP RS		2.7
Varity_R		0.14
gMVP		0.27
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1801582; hg19: chr6-161807855; COSMIC: COSV58214160;